Phenethanolamine derivatives

ABSTRACT

The invention provides compounds of the general formula (I) ##STR1## and physiologically acceptable salts and solvates thereof, wherein Ar represents the group ##STR2## where Q 1  represents a straight or branched C 1-3  alkylene group, ##STR3## where Q 2  represents a group R 3  CO--, R 3  NHCO--, R 3  R 4  NSO 2  -- or R 5  SO 2  --, where R 3  and R 4  each represent a hydrogen atom or a C 1-3  alkyl group, and R 5  represents a C 1-3  alkyl group, ##STR4## R represents a hydrogen atom or a C 1-3  alkyl group; R 1  and R 2  each independently represent a hydrogen atom or a methyl or ethyl group; and k represents an integer from 1 to 8; m represents zero or an integer from 2 to 7, and; n represents an integer from 1 to 7 with the proviso that the sum total of k, m and n is 4 to 12; X represents an oxygen or sulphur atom, and; Y and Z each represent a bond, or an oxygen or sulphur atom with the proviso that when Y is a bond m is zero, or when Y represents an oxygen or sulphur atom m is an integer from 2 to 7, or when Y and Z each independently represent an oxygen or sulphur atom then n is an integer from 2 to 7; Q represents a naphthalenyl group which may optionally be substituted by one or two groups selected from C 1-4  alkyl, C 1-4  alkoxy, hydroxy and halogen. 
     The compounds have a stimulant action at β 2  -adrenoreceptors and may be used in the treatment of diseases associated with reversible airways obstruction such as asthma and chronic bronchitis.

This invention relates to phenethanolamine derivatives having astimulant action at β₂ -adrenoreceptors, to processes for theirpreparation, to pharmaceutical compositions containing them and to theiruse in medicine.

Phenethanolamine derivatives of the general formula ##STR5## in which Arrepresents groupings of the type described hereinafter, and R representsinter alia an alkyl, aralkyl, aryloxyalkyl or an optionally substitutedphenylalkyloxyalkyl group have previously been described asbronchodilators having stimulant activity at β-adrenoreceptors.

Thus, for example, British Patent Specification No. 1200886 describesphenethanolamine compounds of the general structure ##STR6## in which Xrepresents inter alia a hydroxyC₁₋₆ alkyl group; R₁ represents ahydrogen atom or an optionally branched C₁₋₆ alkyl group; R₂ representsinter alia a hydrogen atom; and R₃ represents a hydrogen atom or anoptionally branched C₁₋₆ alkyl group, optionally substituted by hydroxylor amino groups or heterocyclic rings, or R₃ represents a cycloalkyl,aralkyl or aryloxyalkyl group, optionally substituted by one or morealkoxy or hydroxyl groups.

UK Patent Specification No. 2140800 describes phenethanolamine compoundsof the general structure ##STR7## in which R¹ and R² each representhydrogen or C₁₋₃ alkyl; m is an integer from 2 to 8; n is an integerfrom 1 to 7; and Ar represents an optionally substituted phenyl ring.

We have now found a novel group of phenethanolamine derivatives whichdiffer in structure from those described previously (for example,British and UK Patent Specification Nos. 1200886 and 2140800), and havea desirable and potentially useful profile of activity.

Thus the present invention provides compounds of the general formula (I)##STR8## and physiologically acceptable salts and solvates (e.g.hydrates) thereof, wherein Ar represents the group ##STR9## (where Q¹represents a straight or branched C₁₋₃ alkylene group), ##STR10## (whereQ² represents a group R³ CO--, R³ NHCO--, R³ R⁴ NSO₂ -- or R⁵ SO₂ --,where R³ and R⁴ each represent a hydrogen atom or a C₁₋₃ alkyl group,and R⁵ represents a C₁₋₃ alkyl group), ##STR11## R represents a hydrogenatom or a C₁₋₃ alkyl group; R¹ and R² each independently represent ahydrogen atom or a methyl or ethyl group; and k represents an integerfrom 1 to 8; m represents zero or an integer from 2 to 7, and; nrepresents an integer from 1 to 7 with the proviso that the sum total ofk, m and n is 4 to 12; X represents an oxygen or sulphur atom, and; Yand Z each represent a bond, or an oxygen or sulphur atom with theproviso that when Y is a bond m is zero, or when Y represents an oxygenor sulphur atom m is an integer from 2 to 7, or when Y and Z eachindependently represent an oxygen or sulphur atom then n is an integerfrom 2 to 7; Q represents a naphthalenyl group which may optionally besubstituted by one or two groups selected from C₁₋₄ alkyl, C₁₋₄ alkoxy,hydroxy and halogen.

It will be appreciated that the compounds of general formula (I) possessone or more asymmetric carbon atoms. The compounds according to theinvention thus include all enantiomers, diastereoisomers and mixturesthereof, including racemates. Compounds in which the carbon atom in the--CH(OH)-- group is in the R configuration are preferred.

In the general formula (I), the chain --(CH₂)_(k) -- may be for examplea bond, --CH₂ --, --(CH₂)₂ --, --(CH₂)₃ --, --(CH₂)₄ --, --(CH₂)₅ --,--(CH₂)₆ -- or --(CH₂)₇ --. The chains --(CH₂)_(m) -- and --(CH₂)_(n) --may be for example --(CH₂)₂ --, --(CH₂)₃ --, --(CH₂)₄ --, --(CH₂)₅ -- or--(CH₂)₆ -- or the chain --(CH₂)_(m) -- may be a bond.

Preferably the total number of carbon atoms in the chains --(CH₂)_(k)--, --(CH₂)_(m) -- and --(CH₂)_(n) -- is 6 to 12 inclusive. Compoundswherein the sum total of carbon atoms in the chains --(CH₂)_(k) --,--(CH₂)_(m) and --(CH₂)_(n) -- is 6, 7, 8, 9, 10 or 11 are particularlypreferred.

Examples of compounds of general formula (I) are those wherein Xrepresents an oxygen or sulphur atom and Y and Z each represent a bond.Further examples are those wherein X represents an oxygen or sulphuratom, Y represents a bond and Z represents an oxygen or sulphur atom.Still further examples of compounds of general formula (I) are thosewherein X, Y and Z each represent oxygen or sulphur atoms.

A preferred group of compounds of general formula (I) are those in whichX is an oxygen atom. Within this group of compounds Y preferablyrepresents a bond or an oxygen atom and Z represents a bond or an oxygenor sulphur atom.

Preferred compounds from within this group are those wherein X is anoxygen atom, Y is a bond and Z is a bond, or X is an oxygen atom, Y is abond and Z is an oxygen or sulphur atom.

In the compounds of formula (I) R may be, for example, a methyl, ethyl,propyl or isopropyl group. R, R¹ and R² are each preferably a hydrogenatom or a methyl group.

A preferred group of compounds are those in which R represents ahydrogen atom.

Another preferred group of compounds are those wherein R¹ and R² areboth hydrogen atoms, or R¹ is a hydrogen atom and R² is a C₁₋₃ alkylgroup, particularly a methyl group, or R¹ is a methyl group and R² is amethyl group.

In the compounds of formula (I), Q¹ may be, for example, --CH₂ --,--CH(CH₃)--, --(CH₂)₂ -- or --(CH₂)₃ --. A preferred group of compoundsare those in which Q¹ represents --CH₂ --.

Q² may represent for example HCO--, CH₃ CO--, H₂ NCO--, (CH₃)₂ NSO₂ --or CH₃ SO₂ -- Q² preferably represents HCO-- or, more particularly, CH₃SO₂ --.

The group Q is attached to the rest of the molecule through anyavailable position on the naphthalenyl moiety. Any substituent(s) in thegroup Q may be attached to either the same or different rings of thenaphthalenyl moiety. When the group Q is substituted by one or twohalogen atoms, these may be chlorine, fluorine or bromine.

A preferred group of compounds of general formula (I) are those whereinQ is an unsubstituted naphthalenyl moiety attached to the remainder ofthe molecule at the 1- or 2- position.

A further group of preferred compounds of formula (I) are those in whichthe group Q is substituted by a single substituent, for example, amethoxy group.

In one preferred group of compounds of general formula (I) Ar representsgroup (a) wherein Q¹ represents --CH₂ --, or group (b) wherein Q²represents CH₃ SO₂ --, or group (c) or group (d); R represents ahydrogen atom; R¹ represents a hydrogen atom or a methyl group; R²represents a hydrogen atom; X represents an oxygen atom; Y represents abond; Z represents a bond or an oxygen or sulphur atom; and k is 5, m iszero and n is an integer from 1 to 4.

Preferred compounds according to the invention are

4-hydroxy-α¹-[[[6-[2-(2-naphthalenyl)ethoxy]hexy]amino]methyl]-1,3-benzenedimethanol,

4-amino-3,5-dichloro-α-[[[6-[3-(6-methoxy-2-naphthalenyl)propoxy]hexyl]amino]methyl]benzenemethanol,

5-[1-hydroxy-2-[[6-[(2-naphthalenyl)ethoxy]hexyl]amino]ethyl]-1,3-benzenediol,

N-[2-hydroxy-5-[1-hydroxy-2-[[6-[4-[(2-naphthalenyl)oxy]butoxy]hexyl]amino]ethyl]phenyl]methanesulphonamide,and

4-hydroxy-α¹-[[[6-[2-(1-naphthalenyl)ethoxy]hexyl]amino]methyl]-1,3-benzenedimethanol,

and their physiologically acceptable salts and solvates.

Suitable physiologically acceptable salts of the compounds of generalformula (I) include acid addition salts derived from inorganic andorganic acids, such as hydrochlorides, hydrobromides, sulphatres,phosphates, maleates, tartrates, citrates, benzoates,4-methoxybenzoates, 2- or 4-hydroxybenzoates, 4-chlorobenzoates,benzenesulphonates, p-toluenesulphonates, naphthalenesulphonates,methanesulphonates, sulphamates, ascorbates, salicylates, acetates,diphenylacetates, triphenylacetates, adipates, fumarates, succinates,lactates, glutarates, gluconates, tricarballylates,hydroxynaphthalenecarboxylates e.g. 1-hydroxy- or3-hydroxy-2-naphthalenecarboxylates, or oleates. The compounds may alsoform salts with suitable bases where appropriate. Examples of such saltsare alkali metal (e.g. sodium and potassium) and alkaline earth metal(e.g. calcium or magnesium) salts, and salts with organic bases (e.g.triethylamine).

The compounds according to the invention have a stimulant action at β₂-adrenoreceptors, which furthermore is of a particularly advantageousprofile. The stimulant action was demonstrated in the isolated tracheaof the guinea-pig, where compounds were shown to cause relaxation ofcontractions induced by PGF₂ α or electrical stimulation. A prolongedduration of action has also been observed.

The compounds according to the invention may be used in the treatment ofdiseases associated with reversible airways obstruction such as asthmaand chronic bronchitis.

The compounds according to the invention are also indicated as usefulfor the treatment of inflammatory and allergic skin diseases, congestiveheart failure, depression, premature labour, glaucoma, and in thetreatment of conditions in which there is an advantage in loweringgastric acidity, particularly in gastric and peptic ulceration.

The invention accordingly further provides compounds of formula (I) andtheir physiologically acceptable salts and solvates for use in thetherapy or prophylaxis of diseases associated with reversible airwaysobstruction in human or animal subjects.

The compounds according to the invention may be formulated foradministration in any convenient way. The invention therefore includeswithin its scope pharmaceutical compositions comprising at least onecompound of formula (I) or a physiologically acceptable salt or solvatethereof formulated for use in human or veterinary medicine. Suchcompositions may be presented for use with physiologically acceptablecarriers or excipients, optionally with supplementary medicinal agents.

The compounds may be formulated in a form suitable for administration byinhalation or insufflation, or for oral, buccal, parenteral, topical(including nasal) or rectal administration. Administration by inhalationor insufflation is preferred.

For administration by inhalation the compounds according to theinvention are conveniently delivered in the form of an aerosol spraypresentation from pressurised packs, with the use of a suitablepropellant, such as dichlorodifluoromethane, trichlorofluoromethane,dichlorotetrafluoroethane, carbon dioxide or other suitable gas, or froma nebuliser. In the case of a pressurised aerosol the dosage unit may bedetermined by providing a valve to deliver a metered amount.

Alternatively, for administration by inhalation or insufflation, thecompounds according to the invention may take the form of a dry powdercomposition, for example a powder mix of the compound and a suitablepowder base such as lactose or starch. The powder composition may bepresented in unit dosage form in for example capsules or cartridges ofe.g. gelatin, or blister packs from which the powder may be administeredwith the aid of an inhaler or insufflator.

For oral administration, the pharmaceutical composition may take theform of, for example, tablets, capsules, powders, solutions, syrups orsuspensions prepared by conventional means with acceptable excipients.

For buccal administration the composition may take the form of tablets,drops or lozenges formulated in conventional manner.

The compounds of the invention may be formulated for parenteraladministration by bolus injection or continuous infusion. Formulationsfor injection may be presented in unit dosage form in ampoules, or inmulti-dose containers with an added preservative. The compositions maytake such forms as suspensions, solutions or emulsions in oily oraqueous vehicles, and may contain formulatory agents such as suspending,stabilising and/or dispersing agents. Alternatively, the activeingredient may be in powder form for reconstitution with a suitablevehicle, e.g. sterile pyrogen-free water, before use.

For topical administration the pharmaceutical composition may take theform of ointments, lotions or creams formulated in a conventionalmanner, with for example an aqueous or oily base, generally with theaddition of suitable thickening agents and/or solvents. For nasalapplication, the composition may take the form of a spray, formulatedfor example as an aqueous solution or suspension or as an aerosol withthe use of a suitable propellant.

The compounds of the invention may also be formulated in rectalcompositions such as suppositories or retention enemas, e.g. containingconventional suppository bases such as cocoa butter or other glyceride.

Where pharmaceutical compositions are described above for oral, buccal,rectal or topical administration, these may be presented in aconventional manner associated with controlled release forms.

A proposed daily dosage of active compound for the treatment of man is0.005 mg to 100 mg, which may be conveniently administered in one or twodoses. The precise dose employed will of course depend on the age andcondition of the patient and on the route of administration. Thus asuitable dose for administration by inhalation is 0.005 mg to 20 mg, fororal administration is 0.02 mg to 100 mg, and for parenteraladministration is 0.01 mg to 2 mg for administration by bolus injectionand 0.01 mg to 25 mg for administration by infusion.

The compounds according to the invention may be prepared by a number ofprocesses. In the following description, Ar, k, m, n, X, Y, Z, Q, R, R¹and R² are as defined for general formula (I) unless otherwisespecified. In the preparation of both intermediates and end-products thefinal step in the reaction may be the removal of a protecting group.Suitable protecting groups and their removal are described in generalprocess (3) below.

In one general process (1), a compound of general formula (I) may beprepared by alkylation. Conventional alkylation procedures may be used.

Thus, for example, in one process (a), a compound of general formula (I)in which R¹ is a hydrogen atom may be prepared by alkylation of an amineof general formula (II) ##STR12## (wherein R⁶ is a hydrogen atom or aprotecting group and R⁷ is a hydrogen atom) followed by removal of anyprotecting group where present.

The alkylation (a) may be effected using an alkylating agent of generalformula (III): ##STR13## (wherein L is a leaving group, for example ahalogen atom such as chlorine, bromine or iodine, or ahydrocarbylsulphonyloxy group such as methanesulphonyloxy orp-toluenesulphonyloxy).

The alkylation is preferably effected in the presence of a suitable acidscavenger, for example, inorganic bases such as sodium or potassiumcarbonate, organic bases such as triethylamine, diisopropylethylamine orpyridine, or alkylene oxides such as ethylene oxide or propylene oxide.The reaction is conveniently effected in a solvent such as acetonitrileor an ether e.g. tetrahydrofuran or dioxan, a ketone e.g. butanone ormethyl isobutyl ketone, a substituted amide e.g. dimethylformamide or achlorinated hydrocarbon e.g. chloroform, at a temperature betweenambient and the reflux temperature of the solvent.

According to another example (b) of an alkylation process, a compound ofgeneral formula (I) in which R¹ represents a hydrogen atom may beprepared by alkylation of an amine of general formula (II), aspreviously defined except that R⁷ is a hydrogen atom or a groupconvertible thereto under the reaction conditions, with a compound ofgeneral formula (IV):

    R.sup.2 CO(CH.sub.2).sub.k X(CH.sub.2).sub.m Y(CH.sub.2).sub.n Z--Q(IV)

in the presence of a reducing agent, followed when necessary by removalof any protecting groups.

Examples of suitable R⁷ groups convertible into a hydrogen atom arearylmethyl groups such as benzyl, α-methylbenzyl and benzhydryl.

Suitable reducing agents include hydrogen in the presence of a catalystsuch as platinum, platinum oxide, palladium, palladium oxide, Raneynickel or rhodium, on a support such as charcoal, using an alcohol, e.g.ethanol or methanol, or an ester e.g. ethyl acetate, or an ether e.g.tetrahydrofuran, or water, as reaction solvent, or a mixture ofsolvents, e.g. a mixture of two or more of those just described, atnormal or elevated temperature and pressure, for example from 20° to100° C. and from 1 to 10 atmospheres.

Alternatively when one or both of R⁶ and R⁷ are hydrogen atoms, thereducing agent may be a hydride such as diborane or a metal hydride suchas sodium borohydride, sodium cyanoborohydride or lithium aluminiumhydride. Suitable solvents for the reaction with these reducing agentswill depend on the particular hydride used, but will include alcoholssuch as methanol or ethanol, or ethers such as diethyl ether ortert-butyl methyl ether, or tetrahydrofuran.

When a compound of formula (II) where R⁶ and R⁷ are each hydrogen atomsis used, the intermediate imine of formula (V) may be formed: ##STR14##

Reduction of the imine using the conditions described above, followed,where necessary, by removal of any protecting groups, gives compound ofgeneral formula (I).

In another general process (2) compounds of formula (I) may be preparedby reducing an intermediate of general formula (VI): ##STR15## whereinat least one of X¹ and X² represents a reducible group and the other(s)take the appropriate meaning as follows, which is X¹ is --CH(OH)-- andX² is --CHRNR⁶ -- (where R⁶ represents a hydrogen atom or a protectinggroup), followed where necessary by removal of any protecting groups.

Suitable reducible groups include those wherein X¹ is a group >C═O andX² is a group --CHRNR⁸ -- (wherein R⁸ represents a group convertible tohydrogen by catalytic hydrogenation, for example an arylmethyl groupsuch as benzyl, benzhydryl or α-methylbenzyl).

The reduction may be effected using reducing agents convenientlyemployed for the reduction of ketones or protected amines.

Thus, for example, when X¹ in general formula (VI) represents a >C═Ogroup this may be reduced to a --CH(OH)-- group using hydrogen in thepresence of a catalyst such as platinum, platinum oxide, palladium,palladium oxide, Raney nickel or rhodium, on a support such as charcoal,using an alcohol e.g. ethanol, an ester e.g. ethyl acetate, an ethere.g. tetrahydrofuran, or water, as reaction solvent, or a mixture ofsolvents, e.g. a mixture of two or more of those just described, atnormal or elevated temperature and pressure, for example from 20° to100° C. and from 1 to 10 atmospheres. Alternatively, the reducing agentmay be, for example, a hydride such as diborane or a metal hydride suchas lithium aluminium hydride, sodium bis(2-methoxyethoxy) aluminiumhydride, sodium borohydride or aluminium hydride. The reaction may beeffected in an appropriate solvent, such as an alcohol e.g. methanol orethanol, or an ether such as tetrahydrofuran, or a halogenatedhydrocarbon such as dichloromethane.

When X² in general formula (VI) represents a --CHRNR⁸ group this may bereduced to a --CHRNH-- group using hydrogen in the presence of acatalyst as described above.

Where it is desired to use a protected intermediate of general formula(VI) it is particularly convenient to use a protecting group R⁶ which iscapable of being removed under the reducing conditions, for examplehydrogen and a catalyst, thus avoiding the need for a separatedeprotection step. Suitable protecting groups of this type includearylmethyl groups such as benzyl, benzhydryl and α-methylbenzyl.

In the above reduction process, and also in the preparation ofintermediates, care must be taken when using a hydride reducing agentand end-products are required in which Q² represents the group R³ CO--.

In a further process (3) compounds of formula (I) may be prepared bydeprotecting an intermediate of general formula (VII) ##STR16## whereinR⁶ is a protecting group, and/or at least one of the hydroxy group(s) inAr is protected, and/or the group Q contains a protecting group.

The protecting group may be any conventional protecting group asdescribed for example in "Protective Groups in Organic Synthesis", byTheodora Greene (John Wiley and Sons Inc, 1981). Thus, for example,hydroxyl groups may be protected by arylmethyl groups such as benzyl,diphenylmethyl or triphenylmethyl, by acyl groups such as acetyl, or astetrahydropyranyl derivatives. Examples of suitable amino protectinggroups include arylmethyl groups such as benzyl, α-methylbenzyl,diphenylmethyl or triphenylmethyl, and acyl groups such as acetyl,trichloroacetyl or trifluoroacetyl.

The deprotection to yield a compound of general formula (I) may beeffected using conventional techniques. Thus for example arylmethylgroups may be removed by hydrogenolysis in the presence of a metalcatalyst (e.g. palladium on charcoal). Tetrahydropyranyl groups may becleaved by hydrolysis under acidic conditions. Acyl groups may beremoved by hydrolysis with an acid such as a mineral acid e.g.hydrochloric acid, or a base such as sodium hydroxide or potassiumcarbonate, and a group such as trichloroacetyl may be removed byreduction with, for example, zinc and acetic acid.

Intermediates of formula (VI) for use in the reduction process (2) inwhich X¹ is the group >C═O may be prepared by reaction of a haloketoneof formula (VIII) ##STR17## (where Hal represents a halogen atom e.g.bromine) with an amine of formula (IX) ##STR18## (where R⁶ is a hydrogenatom or a group convertible thereto by catalytic hydrogenation).

The reaction may be effected in a cold or hot solvent, for exampletetrahydrofuran, tert-butyl methyl ether, dioxan, chloroform,dichloromethane, dimethylformamide, acetonitrile, a ketone such asbutanone or methylisobutylketone, or an ester such as ethyl acetate,preferably in the presence of a base such as diisopropylethylamine,sodium carbonate or other acid scavenger such as propylene oxide.

Intermediates of general formula (VI) in which X¹ is the group >C═O maybe reduced to the corresponding intermediate in which X¹ is the group--CH(OH)-- using for example a metal hydride such as sodium borohydridein a solvent e.g. ethanol, methanol and/or tetrahydrofuran.

Amines of formula (II) and haloketones of formula (VIII) are eitherknown compounds or may be prepared by methods analogous to thosedescribed for the preparation of known compounds.

Intermediates of formula (III) may be prepared from the correspondingalcohols of formula (X) using methods capable of effecting theconversion ##STR19##

For example compounds of formula (III) where L represents a halogen atommay be prepared by reaction of the compounds of formula (X) with ahalogenating agent such as a triphenylphosphinetetrahalogenomethaneadduct (conveniently formed in situ e.g. by the reaction oftriphenylphosphine and carbon tetrabromide). The reaction may take placein the presence of a solvent such as a chlorinated hydrocarbon (e.g.dichloromethane) at a temperature range of 0°-30°.

Alcohols of formula (X) may be prepared by reacting a compound offormula (XI)

    L═(CH.sub.2).sub.m Y(CH.sub.2).sub.n Z═Q           (XI)

(where L is as defined above) with a compound of formula (XII) ##STR20##

The reaction may take place optionally in a solvent such as an ether(e.g. tetrahydrofuran or 1,2-dimethoxyethane), an alcohol (e.g.methanol) or an amide (e.g. dimethylformamide) at a temperature up tothe boiling point of the solvent. The reaction may be effected by firstgenerating the anion of the compound of general formula (XII) by addingfor example sodium, sodium hydride, potassium hydroxide or sodiumhydroxide.

Compounds of formula (XI) may be prepared from the correspondingcompounds of formula (XIII)

    HO--(CH.sub.2).sub.m Y(CH.sub.2).sub.n Z--Q                (XIII)

using methods capable of effecting the conversion. For example when L ingeneral formula (XI) represents a hydrocarbylsulphonyloxy group (e.g.methanesulphonyloxy) such compounds may be prepared by reacting thecompounds of formula (XIII) with methanesulphonyl chloride in thepresence of a base (e.g. triethylamine). The reaction conveniently takesplace in the presence of a solvent such as a halogenated hydrocarbon(e.g. dichloromethane) at a temperature ranging from 0°-25°.

Compounds of formula (XIII) in which Y represents an oxygen or sulphuratom may be prepared by reacting a compound of formula (XIV) with acompound of formula (XV)

    L--(CH.sub.2).sub.n Z--Q                                   (XIV)

    HO(CH.sub.2).sub.m YH                                      (XV)

under conditions as described for the preparation of compounds offormula (X) above.

Compounds of formula (XIV) are either known compounds or may be preparedfrom the corresponding alcohols as described for the preparation ofcompounds of formula (III) above.

Compounds of formulae (XII) and (XV) are either known compounds or maybe prepared by methods analogous to those used for the preparation ofknown compounds.

In addition, suitable methods for preparing intermediates of formulae(III), (IV), (IX), (XI), (XIII) and (XIV) are described in UK PatentSpecifications Nos. 2140800A and 2159151A and in the exemplificationincluded hereinafter.

In the general processes described above, the compound of formula (I)obtained may be in the form of a salt, conveniently in the form of aphysiologically acceptable salt. Where desired, such salts may beconverted to the corresponding free bases using conventional methods.

Physiologically acceptable salts of the compounds of general formula (I)may be prepared by reacting a compound of general formula (I) with anappropriate acid or base in the presence of a suitable solvent such asacetonitrile, acetone, chloroform, ethyl acetate or an alcohol, e.g.methanol, ethanol or isopropanol.

Physiologically acceptable salts may also be prepared from other salts,including other physiologically acceptable salts, of the compounds ofgeneral formula (I), using conventional methods.

When a specific enantiomer of a compound of general formula (I) isrequired, this may be obtained by resolution of a corresponding racemateof a compound of general formula (I) using conventional methods.

Thus, in one example an appropriate optically active acid may be used toform salts with the racemate of a compound of general formula (I). Theresulting mixture of isomeric salts may be separated for example byfractional crystallisation, into the diastereoisomeric salts from whichthe required enantiomer of a compound of general formula (I) may beisolated by conversion into the required free base.

Alternatively, enantiomers of a compound of general formula (I) may besynthesised from the appropriate optically active intermediates usingany of the general processes described herein.

Specific diastereoisomers of a compound of formula (I) may be obtainedby conventional methods for example, by synthesis from an appropriateasymmetric starting material using any of the processes describedherein, or by conversion of a mixture of isomers of a compound ofgeneral formula (I) into appropriate diastereoisomeric derivatives e.g.salts which then can be separated by conventional means e.g. byfractional crystallisation.

The following examples illustrate the invention. Temperatures are in °C.`Dried` refers to drying using magnesium sulphate or sodium sulphate.Unless otherwise stated, thin layer chromatography (t.l.c.) was carriedout on silica and flash column chromatography (FCC) on silica (Merck9385) using one of the following solvent systems: A--ethylacetate:methanol:triethylamine, B--toluene:ethanol:0.88 ammonia,C--toluene:ethanol:triethylamine. The following abbreviations are used:DMF--dimethylformamide, TAB---tetra-n-butylammonium hydrogen sulphate,DEA--N,N-diisopropylethylamine.

INTERMEDIATE 1 2-[2-[(6-Bromohexyl)oxy]ethyl]naphthalene

2-Naphthaleneethanol (3 g), 1,6-dibromohexane (8 ml), TAB (0.5 g) andsodium hydroxide (8 g) in 16 ml water were stirred at room temperatureunder nitrogen for 26 h Water (80 ml) was added and the mixtureextracted with diethyl ether (3×100 ml). The combined extracts werewashed with water (80 ml), brine (80 ml), dried and evaporated to give acolourless oil (13 g). The oil was purified by FCC eluting withcyclohexane (2 l) and then cyclohexane-ethyl acetate (40:1) to give thetitle compound, (4.23 g), as a colourless oil, t.l.c. (cyclohexaneethylacetate; 5:1) Rf 0.45.

INTERMEDIATE 2 1-[2-[(6-Bromohexyl)oxy]ethyl]naphthalene

1-Naphthaleneethanol (3.00 g) and 1,6-dibromohexane (12.73 g) weretreated according to the method of Intermediate 1. FCC eluting withcyclohexane followed by ethyl acetate-cyclohexane (1:20, then 1:4) gavethe title compound (4.32 g) as a colourless oil.

Analysis Found: C,64.5; H,6.65; Br,23.75. C₁₆ H₂₅ BrO requires C,64.5;H,6.9; Br,23.85%.

INTERMEDIATE 3 1-[[(5-Bromopentyl)oxy]methyl]naphthalene

1-Naphthalenemethanol (6.00 g) and 1,5-dibromopentane (11.5 ml) weretreated according to the method of Intermediate 1. FCC eluting withether-cyclohexane (1:49→2:48) gave the title compound as a colourlessoil (8.41 g), t.l.c. (Cyclohexane-ether 19:1) Rf 0.22;

INTERMEDIATE 4 7-[(1-Naphthalenyl)methoxy]-2-heptanone

1-[[(5-Bromopentyl)oxy]methyl]naphthalene (9.96 g) in dry ether (40 ml)was added to magnesium turnings (0.94 g) and iodine (one small crystal)under nitrogen with stirring at a rate which maintained a gentle reflux.The mixture was stirred at reflux for 30 min, cooled to ambienttemperature and added over 2.5 h to acetic anhydride (7.67 ml) in ether(15 ml) at -78° under nitrogen with vigorous stirring. After 2 h at-78°, the mixture was allowed to warm to -10° and treated with aqueoussaturated ammonium chloride (50 ml). Ether (50 ml) was added, theaqueous layer was separated and the ethereal layer was washed with1M-aqueous sodium hydroxide (100 ml). The combined aqueous washings wereextracted with ether (100 ml) and this extract was combined with theethereal layer above. The dried ethereal solution was evaporated and theresidual oil purified FCC. Elution with ether-cyclohexane (1:4) gave,after Kugelrohr distillation, the title compound as a colourless oil(3.39 g), b.p. 190°/0.3 Torr (Kugelrohr).

INTERMEDIATE 5N-[6-[[3-[6-Methoxy-2-naphthalenyl]-2-propynyl]oxy]hexyl]benzenemethanamine

Nitrogen was bubbled through a mixture ofN-[6-[(2-propynyl)oxy]hexyl]benzenemethanamine (4.14 g),2-bromo-6-methoxynaphthalene (4.0 g) and dicyclohexylamine (5.82 g) inacetonitrile (60 ml) for 15 min. Bis(triphenylphosphine)palladium (II)chloride (120 mg) and copper (I) iodide (10 mg) were added and themixture was stirred at reflux under nitrogen for 4 h, cooled, dilutedwith ether (100 ml), filtered and the filtrate evaporated in vacuo.Purification by FCC eluting with System B (90:10:1) gave the titlecompound as a brown oil (1.18 g), t.l.c. (System B 40:10:1) Rf 0.19.

INTERMEDIATE 6(Z)-N-[5-[1-Hydroxy-2-[[6-[3-(6-methoxy-2-naphthalenyl)-2-propenyloxy]hexyl](phenylmethyl)amino]ethyl]-2-(phenylmethoxy)phenyl]methanesulphonamide

A solution ofN-[5-(bromoacetyl)-2-(phenylmethoxy)phenyl]methanesulphonamide (0.96 g),N-[6-[3-(6-methoxy-2-naphthalenyl)-2-propynyloxy]hexyl]benzenemethanamine(1.38 g) and DEA (0.47 g) in dichloromethane (22 ml) was stirred at roomtemperature under nitrogen for 22 h, diluted with water (100 ml) andextracted with dichloromethane (2×100 ml). The combined organic extractswere dried and evaporated in vacuo to give an oil. The oil was dissolvedin methanol (20 ml) and dichloromethane (20 ml) and sodium borohydride(0.25 g) were added portionwise to the solution at 0° C. under nitrogen.The solution was stirred at room temperature for 1 h, cooled to 0° C.and a further portion of sodium borohydride (0.1 g) added. The solutionwas stirred at room temperature for 30 min and then carefully dilutedwith water (10 ml) and evaporated in vacuo. The residue was partitionedbetween dichloromethane (100 ml) and water (100 ml). The aqueous phasewas re-extracted with dichloromethane (100 ml) and the combined organicfractions dried and evaporated in vacuo to give an oil. Purification byFCC eluting with System C (100:2:1) gave the title compound as acolourless oil (0.77 g), t.l.c. (System C 98:2:1) Rf 0.23.

INTERMEDIATE 74-Amino-3,5-dichloro-α-[[[6-[[3-[6-methoxy-2-naphthalenyl]-2-propynyl]oxy]hexyl](phenylmethyl)amino]methyl]benzenemethanol

A solution of 1-(4-amino-3,5-dichloro)-2-bromoethanone (0.78 g),N-[6-[[3-[6-methoxy-2-naphthalenyl]-2-propynyl]oxy]hexyl]benzenemethanamine(1.1 g) and DEA (0.39 g) in tetrahydrofuran (25 ml) was stirred undernitrogen for 20 h. The mixture was filtered and the filtrate evaporatedin vacuo to give an oil. The oil was dissolved in methanol (20 ml) anddichloromethane (30 ml) and sodium borohydride (0.28 g) addedportionwise to the solution at 0° C. under nitrogen. The solution wasstirred at room temperature for 2 h, cooled to 0° C. and a furtherportion of sodium borohydride (0.14 g) added. The solution was thenstirred at room temperature for 1 h, carefully diluted with water (10ml) and evaporated in vacuo. The residue was partitioned between ethylacetate (100 ml), water (100 ml), the aqueous phase was re-extractedwith ethyl acetate (100 ml) and the combined organic fractions dried andevaporated in vacuo to give an oil. Purification by FCC eluting withSystem C (100:1:1) gave the title compound as a colourless oil (1.18 g),t.l.c (System C 98:2:1) Rf 0.53.

INTERMEDIATE 8 4-[(2-Naphthalenyl)oxy]butanol

A mixture of 2-[(4-bromobutyl)oxy]naphthalene (5.5 g), sodium acetate(13.1 g), trioctylpropylammonium chloride (1.21 g) and water (19 ml) wasstirred at ca 100° for 2 h. 2N sodium hydroxide solution (32 ml) andethanol (32 ml) were added to the cooled mixture which was stirred for afurther 10 min at room temperature. The ethanol was evaporated in vacuoand the residue diluted with brine (150 ml) and extracted with ether(2×100 ml), which was dried and evaporated in vacuo to give a whitesolid. The solid was dissolved in ether and purified by FCC eluting withhexane-ether (2:1→1:2) to give the title compound as a white solid (1.36g), m.p. 66.5°-67.5°.

INTERMEDIATE 9 2-[4-[(6-Bromohexyl)oxy]butoxy]naphthalene

A mixture of 4-[(2-naphthalenyl)oxy]butanol (2.4 g), 1.6-dibromohexane(5.3 ml), TAB (1 g) and 50% sodium hydroxide solution (24 ml) wasstirred at room temperature for 19 h. The mixture was diluted with water(100 ml) and extracted with ether (2×150 ml). The combined organicfractions were dried and evaporated in vacuo to give an oil.Purification by FCC eluting with hexane followed by hexane-ether(19:1→8:1) gave the title compound as a colourless oil, (2.34 g), t.l.c.(ether-hexane 1:1) Rf 0.85.

INTERMEDIATE 10N-[6-[4-[(2-Naphthalenyl)oxy]butoxy]hexyl]benzenemethanamine

2-[4-[(6-Bromohexyl)oxy]butoxy]naphthalene (2.25 g) and benzylamine(3.88 g) were stirred under nitrogen at ca. 125° for 2 h. The solutionwas diluted with 8% sodium bicarbonate (100 ml) and extracted withdiethyl ether (2×100 ml), dried and evaporated in vacuo to give an oil.Purification by FCC eluting with System C (98:2:1) gave the titlecompound as a yellow oil (2.3 g), t.l.c. (System C 40:10:1) Rf 0.71.

INTERMEDIATE 11 2-[[2-[(6-Bromohexyl)oxy]ethyl]thio]naphthalene

A mixture of 1,6-dibromohexane (9 ml), 50% w/v sodium hydroxide (40 ml),2-(2-naphthalenyl)thioethanol (4 g), TAB (0.8 g) and hexane (30 ml) wasstirred vigorously at 20°, under nitrogen for 4 h. Water (100 ml) andether (100 ml) were added and the mixture was further extracted withether (100, 2×50 ml). The combined, dried ether extracts were evaporatedin vacuo to give a yellow oil. Purification by FCC eluting with lightpetroleum (b.p. 60°-80°):ether (30:1→1:1) gave the title compound as awhite crystalline solid (5.7 g), m.p. 38°-40° (softens 36°).

EXAMPLE 1 4-Hydroxy-α¹-[[[6-[2-(2-naphthalenyl)ethoxy]hexyl]amino]methyl]-1,3-benzenedimethanol

α¹ -(Aminomethyl)-4-hydroxy-1,3-benzenedimethanol (1.31 g),2-[2-[(6-bromohexyl)oxy]ethyl]naphthalene (2 g) and DEA (0.83 ml) in DMF(dried over type 4 Å sieves, 20 ml) were stirred at 100° under nitrogenfor 2 h. The cooled mixture was poured into aqueous saturated sodiumbicarbonate (80 ml) and extracted with ethyl acetate (3×100 ml). Thecombined extracts were washed (water, 100 ml), dried and evaporated togive a yellow tacky solid (3.5 g). This solid was adsorbed onto silica(Merck 7734, 2 g) from methanol and the resultant silica gel plug wasapplied to an FCC column. Elution with System A (89:10:1) gave a whitesolid (0.95 g), which crystallised from ethyl acetate (20 ml) to givethe title compound (0.32 g) as a white solid, m.p. 112°-114°.

Analysis Found: C,73.3; H,8.2; N,3.1. C_(2/) H₃₅ NO₄.0.2H₂ O requiresC,73.5; H,8.1; N,3.2%.

Water analysis, 0.2 mole water.

EXAMPLE 2 4-Hydroxy-α¹-[[[6-[2-(1-naphthalenyl)ethoxy]hexyl]amino]methyl]-1,3-benzenedimethanol

A mixture of α¹ -(aminomethyl)-4-hydroxy-1,3-benzenedimethanol (0.75 g),1-[2-[(6-bromohexyl)oxy]ethyl]naphthalene (1.00 g), DEA (0.85 ml) in DMF(6.5 ml) was heated at 80° for 2 h. The clear brown solution was dilutedwith water (65 ml), acidified to pH 4 with 2N hydrochloric acid and thenbasified to pH 8 with solid potassium bicarbonate. The mixture wasextracted with ethyl acetate (2×65 ml) and the combined extracts werewashed with water (65 ml) and brine (30 ml). The dried extracts wereevaporated, the residue dissolved in ethyl acetate-methanol (1:1) andabsorbed onto silica (Merck 7734, 5.00 g). The silica gel plug wasapplied to an FCC column and elution with System A (90:10:1) gave thetitle compound (0.22 g) as a white solid m.p. 105°-107°.

Analysis Found: C,73.1; H,7.85; N,3.1. C_(2/) H₃₅ NO₄ 0.33H₂ O requiresC,73.1; H,8.1; N,3.1%.

EXAMPLE 3 4-Hydroxy-α¹-[[[1-methyl-6-[[(1-naphthalenyl)methyl]oxy]hexyl]amino]methyl]-1,3-benzenedimethanol

7-[(1-naphthalenyl)methoxy]-2-heptanone (1.00 g) and α¹-[[bis(phenylmethyl)amino]methyl]-4-hydroxy-1,3-benzenedimethanol (1.34g) in ethanol (40 ml) were hydrogenated over pre-reduced 10% palladiumoxide-on-carbon (0.2 g) and 5% platinum oxide-on-carbon (0.2 g) at roomtemperature and pressure. The catalyst was removed (hyflo) and thesolution evaporated. The residual oil was purified by FCC, eluting withSystem A (94:5:1) to give a white solid (704 mg). The white solid wasfurther purified by repeating the chromatography procedure to give thetitle compound as a white solid (469 mg) m.p. 99°-101°.

Analysis Found: C,73.7; H,8.5; N,3.15. C_(2/) H₃₅ NO₄ requires C,74.1;H,8.05; N,3.2%.

EXAMPLE 4N-[2-Hydroxy-5-[1-hydroxy-2-[[6-[3-(6-methoxy-2-naphthalenyl)propoxy]hexyl]amino]ethyl]phenyl]methanesulphonamide

A solution ofZ-N-[5-[1-hydroxy-2-[6-[3-(6-methoxy-2-naphthalenyl)-2-propenyloxy]hexyl](phenylmethyl)amino]methyl]benzenemethanol(0.73 g) in absolute ethanol (30 ml) was hydrogenated over pre-reduced10% palladium on charcoal catalyst (0.4 g) in absolute ethanol (10 ml).The mixture was filtered through hyflo and evaporated in vacuo. Theresultant solid was dissolved in dichloromethane (50 ml) and washed with8% sodium bicarbonate (50 ml). The aqueous phase was re-extracted withdichloromethane (50 ml) and the combined organic extracts dried andevaporated in vacuo to give a solid. Trituration with diethyl ether gavethe title compound as an off-white solid (0.25 g), m.p. 87°-89°.

Analysis Found: C,63.2; H,7.1; N,5.1. C₂₉ H₄₀ N₂ O₆ S.0.25H₂ O requiresC,63.4; H,7.4; N,5.1%.

EXAMPLE 54-Amino-3,5-dichloro-α-[[[6-[3-(6-methoxy-2-naphthalenyl)propoxy]hexyl]amino]methyl]benzenemethanol

A solution of4-amino-3,5-dichloro-α-[[[6-[[3-[6-methoxy-2-naphthalenyl]-2-propynyl]oxy]hexyl](phenylmethyl)amino]methyl]benzenemethanol(1.11 g) in absolute ethanol (50 ml) was hydrogenated over pre-reduced10% palladium on charcoal catalyst (0.4 g) in absolute ethanol (10 ml)containing hydrochloric acid (1:9 conc. hydrochloric acid/ethanol, 1.67ml). The mixture was filtered through hyflo and evaporated in vacuo togive an oil. The oil was partitioned between dichloromethane (150 ml)and 8% sodium bicarbonate (100 ml). The aqueous phase was re-extractedwith dichloromethane (100 ml) and the combined organic extracts driedand evaporated in vacuo to give an oil. Purification by FCC eluting withSystem C (95:5:1) gave the title compound as a white solid (513 mg),m.p. 102.5°-103.5°.

Analysis Found: C,64.5; H,7.5; N,5.3; Cl,13.9. C₂₈ H₃₆ Cl₂ N₂ O₃requires C,64.7; H,7.0; N,5.4; Cl,13.6%.

EXAMPLE 65-[1-Hydroxy-2-[[6-[(2-naphthalenyl)ethoxy]hexyl]amino]ethyl]-1,3-benzenediol,4,4'-methylenebis[3-hydroxy-2-naphthalenecarboxylate](2:1) salt

A mixture of 5-(2-amino-1-hydroxyethyl)-1,3-benzenediol (1.02 g),2-[3-[(6-bromohexyl)oxy]ethyl]naphthalene (1.34 g) and DEA (1.74 ml) inDMF (25 ml) was heated at 100° for 3 h under nitrogen. The solvent wasremoved in vacuo and the residue purified by FCC eluting with System B(80:20:1) to give the base as a solid pink glass (0.8 g).

A mixture of the base (0.4 g) and4,4'-methylenebis[3-hydroxy-2-naphthalenecarboxylic acid] (0.18 g) inmethanol (30 ml) was heated under reflux for 30 min. The methanol wasremoved in vacuo and the residue triturated under ether (20 ml) to givethe title compound as an off-white solid (0.52 g), m.p. 105°-110°(softens 100°).

Analysis Found: C,70.2; H,6.9; N,2.1. (C₂₆ H₃₃ NO₄)₂ C₂ H₁₆ O₆.2.5H₂ Orequires C,70.35; H,6.85; N,2.2%.

EXAMPLE 7N-[2-Hydroxy-5-[1-hydroxy-2-[[6-[4-[(2-naphthalenyl)oxy]butoxy]hexyl]amino]ethyl]phenyl]methanesulphonamide

A solution ofN-[5-(bromoacetyl)-2-phenylmethoxy)phenyl]methanesulphonamide (1.96 g),N-[6-[4-[(2-naphthalenyl)oxy]butoxy]hexyl]benzenemethanamine (2.0 g) andDEA (0.96 g) in dichloromethane (45 ml) was stirred under nitrogen atroom temperature for 22 h. The mixture was treated with water (100 ml)and extracted with dichloromethane (2×150 ml). The combined organicextracts were dried and evaporated in vacuo to give an oil which wasdissolved in methanol (30 ml) and dichloromethane (20 ml) and cooled to0°-5° C. under nitrogen. Sodium borohydride (0.50 g) was addedportionwise and the solution stirred at room temperature for 30 min,then carefully diluted with water (20 ml). The solvent was evaporated invacuo, the residue partitioned between water (100 ml) anddichloromethane (150 ml) and the aqueous phase re-extracted withdichloromethane (150 ml), the combined organic extracts being dried andevaporated in vacuo to give an oil which was purified by FCC elutingwith System C (95:5:1). A solution of the oil (3.41 g) in absoluteethanol (60 ml) was hydrogenated over pre-reduced 10% palladium oncharcoal catalyst (50% aqueous paste, 1.5 g) in absolute ethanol (10 ml)for 4.5 h. The mixture was filtered through hyflo and evaporated invacuo to give an oil which was purified by FCC eluting with System B(40:10:1) to give a cream solid. Trituration with diethyl ether gave thetitle compound as a white solid (1.23 g), m.p. 99.5°-100.5°.

Analysis Found: C,64.1; H,7.3; N,5.2. C₂₉ H₄₀ N₂ O₆ S requires C,63.9;H,7.4; N,5.1%.

EXAMPLE 8N-[2-Hydroxy-5-[1-hydroxy-2-[[6-[4-[(2-naphthalenyl)oxy]butoxy]hexyl]amino]ethyl]phenyl]methanesulphonamide,4,4'-methylenebis[3-hydroxy-2-naphthalenecarboxylate] salt (2:1)

A solution ofN-[2-hydroxy-5-[2-hydroxy-2-[[6-[4-[(2-naphthalenyl)oxy]butoxy]hexyl]amino]ethyl]phenyl]methanesulphonamide(449 mg) in methanol (17 ml) and4,4'-methylenebis[3-hydroxy-2-naphthalenecarboxylic acid] (160 mg), washeated at reflux for 1 h, cooled, filtered and the filtrate evaporatedin vacuo. The residue was triturated with dry ether to afford the titlecompound as an off-white foam (413 mg), m.p. 100°-106°.

Assay Found: C,65.0; H,6.6; N,3.7; S,4.2. C₂₉ H₄₀ N₂ O₆ S.0.5C₂₃ H₁₆O₆.0.5H₂ O requires C,65.0; H,6.6; N,3.75; S,4.3%.

EXAMPLE 9 4-Hydroxy-α¹-[[[6-[2-[(2-naphthalenyl)thio]ethoxy]hexyl]amino]methyl]1,3-benzenedimethanol

A solution of α¹ -(aminomethyl)-4-hydroxy-1,3-benzenedimethanol (1.0 g),2-[[2-[(6-bromohexyl)oxy]ethyl]thio]naphthalene (1.01 g) and DEA (0.52g) in dry DMF (30 ml) was stirred at 100° under nitrogen for 4 h. Thesolvent was evaporated and the residue purified by FCC eluting withSystem B (39:10:1) to give a pale brown solid (0.76 g). Triturationunder ether (2×50 ml) gave the title compound as a cream coloured solid(0.39 g), m.p. 101°-2°.

Analysis Found: C,68.9; H,7.6; N,3.0; S,6.6. C_(2/) H₃₅ NO₄ S requiresC,69.05; H,7.5; N,3.0; S,6.8%.

The following are examples of suitable formulations of compounds of theinvention. The term `active ingredient` is used herein to represent acompound of the invention.

Tablets (Direct Compression)

    ______________________________________                                                          mg/tablet                                                   ______________________________________                                        Active Ingredient    2.0                                                      Microcrystalline cellulose USP                                                                    196.5                                                     Magnesium Stearate BP                                                                              1.5                                                      Compression weight  200.0                                                     ______________________________________                                    

The active ingredient is sieved through a suitable sieve, blended withthe excipients and compressed using 7 mm diameter punches.

Tablets of other strengths may be prepared by altering the ratio ofactive ingredient to microcrystalline cellulose or the compressionweight and using punches to suit.

The tablets may be film coated with suitable film forming materials,such as hydroxypropylmethylcellulose, using standard techniques.Alternatively, the tablets may be sugar coated.

Metered Dose Pressurised Aerosol (Suspension Aerosol)

    ______________________________________                                                      mg/metered dose                                                                            Per can                                            ______________________________________                                        Active Ingredient                                                                             0.100          26.40  mg                                      micronised                                                                    Oleic Acid BP   0.100          2.64   mg                                      Trichlorofluoromethane BP                                                                     23.64          5.67   g                                       Dichlorodifluoromethane BP                                                                    61.25          14.70  g                                       ______________________________________                                    

The active ingredient is micronised in a fluid energy mill to a fineparticle size range. The oleic acid is mixed with thetrichlorofluoromethane at a temperature of 10°-15° C. and the microniseddrug is mixed into the solution with a high shear mixer. The suspensionis metered into aluminium aerosol cans and suitable metering valvesdelivering 85 mg of suspension are crimped onto the cans and thedichlorodifluoromethane is pressure filled into the cans through thevalves.

Inhalation Cartridges

    ______________________________________                                                         mg/cartridge                                                 ______________________________________                                        Active ingredient micronised                                                                     0.200                                                      Lactose BP to      25.0                                                       ______________________________________                                    

The active ingredient is micronised in a fluid energy mill to a fineparticle size range prior to blending with normal tabletting gradelactose in a high energy mixer. The powder blend is filled into No. 3hard gelatin capsules on a suitable encapsulating machine. The contentsin the cartridges are administered using a powder inhaler such as theGlaxo Rotahaler.

We claim:
 1. A compound of formula ##STR21## or a physiologicallyacceptable salt or solvate thereof, wherein Q represents a 1- or2-naphthalenyl group.
 2. A compound comprising 4-Hydroxy-α¹[[[6-[2-(2-naphthalenyl)ethoxy]hexyl]amino]methyl]-1,3-benzenedimethanol or a physiologicallyacceptable salt or solvate thereof.
 3. A compound comprising4-Hydroxy-α¹ [[[6-[2-(1-naphthalenyl)ethoxy]hexyl]amino]methyl]-1,3-benzenedimethanol or a physiologicallyacceptable salt or solvate thereof.
 4. A pharmaceutical composition fortherapy or prophylaxis of a disease associated with reversible airwaysobstruction such as asthma or chronic bronchitis, which comprises aneffective amount to alleviate said disease of at least one compound offormula (I) as defined in claim 1 or a physiologically acceptable saltor solvate thereof, together with a physiologically acceptable carrieror excipient.